One of the most well-known and widely-used classes of antibacterial agents is the class known as the .beta.-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting or a 2-azetidinone (.beta.-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the .beta.-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given .beta.-lactam antibiotic results because the microorganism produces a .beta.-lactamase. The latter substances are enzymes which cleave the .beta.-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit .beta.-lactamases, and when a .beta.-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a .beta.-lactamase inhibiting substance and a .beta.-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components.
Thus, according to the invention, there are provided certain new chemical compounds which are potent inhibitors of microbial .beta.-lactamases. More specifically, these new chemical compounds are 2.beta.-acetoxymethyl-2.alpha.-methyl-(5R)-penam-3.alpha.-carboxylic acid 1,1-dioxide, pharmaceutically-acceptable salts thereof and esters thereof readily hydrolyzable in vivo. Additionally, there is provided a method for enhancing the effectiveness of .beta.-lactam antibiotics using said new chemical compounds, and pharmaceutical compositions comprising said new chemical compounds. Yet further, according to the invention, there are provided certain compounds useful as intermediates to said novel .beta.-lactamase inhibitors.
Several penicillin derivatives were tested as potential .beta.-lactamase inhibitors by Chaikovskaya et al., Antibiotiki, 13, 155 (1968); benzylpenicillin 1,1-dioxide was found to be inactive. Penam compounds having an acetoxymethyl group at the 2-position are disclosed by Morin et al., Journal of the American Chemical Society, 91, 1401 (1969), and by Barton et al., Journal of the Chemical Society (London) Part D, 1683 (1970); ibid. Part C, 3540 (1971). Deamination of 6-aminopenicillanic acid in the presence of acetic acid gives 6.alpha.-acetoxypenicillanic acid, which was converted into its methyl ester using diazomethane (Hauser and Sigg, Helvetica Chimica Acta, 50, 1327 [1967]). Penicillanic acid is disclosed in British Pat. No. 1,072,108.
West German Offenlegungsschrift No. 2,824,535, published Dec. 14, 1978, and Iranian Pat. No. 19,601, granted July 12, 1978, disclose penicillanic acid 1,1-dioxide, and esters thereof readily hydrolyzable in vivo, as antibacterial agents and as .beta.-lactamase inhibitors. Penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo increase the antibacterial effectivness of certain penicillin and cephalosporin compounds against certain bacteria.